Phase I Trial of Maintenance Sorafenib after Allogeneic HSCT for Patients with FLT3-ITD AML

Introduction: The presence of the FLT3-ITD (internal tandem duplication) mutation in patients with AML is associated with an adverse prognosis.  Even with allogeneic hematopoietic stem cell transplantation (HSCT), disease relapse remains the biggest obstacle to success.  Sorafenib is an oral tyrosine kinase inhibitor which has been shown to inhibit the FLT3 tyrosine kinase and have activity against FLT3-ITD AML. 

Methods: We are conducting a phase I clinical trial of maintenance sorafenib in patients with FLT3-ITD AML after HSCT.  Any conditioning regimen and any donor source are allowed.  A dose escalation 3+3 cohort design was used to define the maximum tolerated dose (MTD) of sorafenib after HSCT with an additional 10 patients treated at the defined MTD.  Sorafenib was initiated between days 45 and 120 after HSCT and given continuously for twelve 28-day cycles.  All patients were proven to be in morphological CR after HSCT and without any active acute graft-vs-host disease prior to starting sorafenib.

Results: We have thus far enrolled 18 patients (CR1=12, CR2=3, Refractory=3). 10 patients underwent myeloablative conditioning and 8 patients received reduced intensity conditioning. Donors included matched related or unrelated donors (n=16), cord blood (n=1), and haploidentical (n=1).  12 patients were treated in the dose escalation phase: 200 mg BID (n=3), 400 mg AM / 200 mg PM (n=3), and 400 mg BID (n=6), and 6 patients have been treated so far on the expansion phase.  The MTD was established at 400 mg BID with only one DLT observed (pericardial effusion) at the 400 mg BID dose level (the highest planned dose).  Two patients experienced early transplant-related mortality - one case of idiopathic pneumonitis and one case of cirrhosis.  Neither of these deaths was deemed to be related to sorafenib.  One patient has stopped sorafenib after disease relapse and five patients have stopped sorafenib due to toxicity (skin, GI, weight loss, tongue swelling).  No cases of grades II-IV acute GVHD were observed after starting sorafenib and 1-year cumulative incidence of chronic GVHD is 42% (95% CI 0.14, 0.69), which is similar to our historical controls.  In the entire cohort, there have been only two cases of disease relapse and both were cases of primary refractory AML prior to HSCT.  Median follow-up for the 14 surviving patients is 10.9 months (range, 2.2-25.8) after transplant.  One-year progression-free survival is 84% (95% CI 0.49, 0.96) and one-year OS is 93% (95% CI 0.61, 0.99).  No patients who underwent HSCT in CR1 (n=12) or CR2 (n=3) have experienced relapse.  

Conclusion: Sorafenib appears safe to use after HSCT for patients with FLT3-ITD AML.   Compared to historical results, our preliminary results suggest promising progression-free survival with no observed relapses in patients who underwent HSCT in CR.  Maintenance sorafenib after HSCT for FLT3-ITD AML merits further investigation.